The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention.
Topoisomerase I is a nuclear enzyme that plays an important role in cell proliferation. The enzyme catalyzes the uncoiling of DNA during replication and transcription (Pommier, et al., Biochim Biophys Acta 1998; 1400(1-3):83-105; Wang, Annu Rev Biochem 1996; 65:635-92).
The activity of topoisomerase I is regulated by phosphorylation. Such phosphorylation occurs primarily on serine residues (Turman, et al., Biochem Med Metab Biol 1993; 50(2):210-25; Coderoni, et al., Int J Biochem 1990; 22(7):737-46; Kaiserman, et al., Biochemistry 1988; 27(9):3216-22; Samuels, et al., J Biol Chem 1992; 267(16):11156-62) and appears to be necessary for the initial complex formation between the enzyme and the DNA (Coderoni, et al., Int J Biochem 1990; 22(7):737-46).
Human cancers are characterized by uncontrolled proliferation of abnormal cells. Topoisomerase I inhibitors have been used as chemotherapeutic agents that interfere with normal DNA replication and cell division. However, some cancers are not sensitive to such topoisomerase I inhibitors.